Abstract The role that stem or progenitor cells play in promoting cardiac regeneration has been the topic of rigorous scientific discussion over the past 15 years. A number of prominent laboratories have shown data whereby select sources of adult stem/progenitor cells can transdifferentiate and repopulate large areas of infarction or chemically injured myocardium with new cardiomyocytes that fully restore ventricular function. One stem/progenitor cell that has been highly touted as a true cardiac regenerative cell type is that expressing the cell surface marker for cKit (CD117). However, other laboratories have not observed the ability of select progenitors cells or cKit+ CPCs to generate new myocytes by transdifferentiation when injected, nor did they observe appreciable generation of new myocytes from endogenous stem cell sources. The entire field has become a contentious affair these past 5 years with essentially 2 diametrically opposed camps that continue to publish data supportive of their original observations. Hence, here we are proposing a novel approach whereby 2 laboratories from each camp will work together in a blinded manner with full exchange of all reagents and animal models to generate consensus data. This dual-PI application will also rely almost exclusively on mouse genetics and lineage tracing approaches so that more definitive data will arise. The three specific aims will address the overarching hypothesis that injection of exogenous progenitor cells into the heart results in cardioprotection through a paracrine mechanism of action. We will not address the transdifferentiation hypothesis as this seems to have been largely discredited. The paracrine hypothesis involves the generation of new endothelial cells from endogenesis cKit+ CPCs and the enhancement of ventricular perfusion in and around the area of myocardial infarction. It also may involve the augmentation of endogenous myocyte proliferation from existing myocytes, protection of myocytes from apoptosis in the border zone by paracrine factors and protective remodeling of the extracellular matrix, all of which will be investigated as part of the larger ?paracrine hypothesis? A highly structured experimental approach is proposed along with a system for blinded exchanges of biologic samples between the 2 laboratories. The goal is to generate a decisive data set based entirely on more rigorous standards and approaches, with the hope of bringing consensus to the cardiac stem cell field. The 2 PIs have a long track record of working together with multiple shared publications and joint grants.